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IMMUNE RECONSTITUTION

INFLAMMATORY SYNDROME (IRIS)TERKAIT INFEKSI TUBERCULOSIS (TB)DAN VAKSINASI BCG PADA ANAKDENGAN HIVASNI RAHAYU

Article Review

RespirologySubdivision


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HIV-IRIS inchildren

limited data

115.000

Get ART

780.000 need ART

Child with HIV2,5 millions

INTRODUCTION

HIV ARTIRIS ??

76-90% dead infirst 6 mo ART

?


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EPIDEMIOLOGY


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IRIS DEFENITION

Case Definition: Consensus Criteria for Diagnosis of Pediatric IRIS

1. Evidence of clinical response to ART with:

a. Virologic response with >1 log10 copies/mL decrease in HIV RNA (ifpossible).1

2. Clinical deterioration from an infectious or inflammatory conditiontemporally related to the initiation of ARTa. Unmasking IRIS requires a new active diagnosis2b. For Paradoxical TB-IRIS, refer to Table 3 for clinical criteria

3. Symptoms cannot be explained by:a. An alternate infection or neoplasmb. Treatment failure of the opportunistic infection.3c. Adverse drug reactiond. Complete non-compliance to ART or TB treatment4

1

IRIS can occur in the absence of a meaningful rise in CD4 count. In ART nave persons, an initial virologic response generally alwaysoccurs. In nonnave persons or with known ART resistance, proof of virologic response becomes more important.2

Unmasking caveats: Active infections, such as TB, should be excluded at time of ART initiation. Diagnosis of incident TB infections should conform to national or WHO guidelines. In children, bacteriologic confirmation may not

always be achieved. Unmasked incident infections may have accelerated presentations with exaggerated symptoms. Refeeding syndrome of malnourished children may contribute to unmasking opportunistic infections . Generally occurs within 6 months after ART initiation.3

Paradoxical IRIS can occur with MDR and XDR TB; however, the primary concern is the efficacy of the TB therapy. For TB-IRIS, non

compliance and TB treatment failure are critical to exclude.4

Even with imperfect ART compliance and lack of HIV virologic suppression, immunologic reconstitution and CD4 rise can occur


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Innateimmunedetection ofHIV PAMPs.

(pathogen-associatedmolecularpatterns)

Model of the HIV

life cycle andinteractionsbetween HIV andinnate immunity:-Detection ofHIV by any of

these threeinnate immunepathwaysactivates genesfor IFN-a.

Yan and Lieberman

2011

HIV RNA

CA=nascent capsid protein

Most striking early events are related to activation of the IFN-a and Interferon


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IRISPathophysiology

CD4 response to HAART1st:Rapid redistribution of CD4 memorycells from peripheral lymphoid tissue

Then: More gradual restoration of nave

CD4 cells from thymus Dyregulated responseShift to Th1 pro-inflammatory cytokine

profile

Lack of immune regulation Inability to produce regulatory cytokines High burden of offending antigen


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Common Scenarios of HIV Immune Reconstitution InflammatorySyndrome (IRIS)

Unmasking IRIS Occult, subclinical opportunistic infection Unmasked by immune recovery following ART initiation Infectious pathogen typically detectable

Paradoxical IRIS Clinical recrudescence of a successfully treated infection Symptomatic relapse despite initial clinical improvement andcontinued microbiologic treatment success. Antigen driven immune activation, often with a robust immune

response in the setting of few or no detectable organisms. Culture may be sterile due to effective opportunistic infectiontreatment


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Paradoxical IRIS Exacerbation and/or

return of symptoms ofcurrently or recentlytreated OI

Non-viable antigens ofpathogens

Usually 3 months ofHAART

Months to years forimmune recovery

(CMV) uveitis Examples: TB,Cryptococcal disease,Kaposis sarcoma (KS)

Unmasking IRIS Clinical

presentation ofpreexisting,subclinical OIafter HAART

initiation Viable pathogens Usually 3

months of HAART

Example: Non-tuberculousmycobacteria(MAC), TB


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HIV / TB COINFECTION

HIGH TB PREV.

TB IRIS INCIDEN 3,4 %

HIV PREV. 1-

70 %10 %

CHILDREN.

UNMASKING TB 6,2 %FROM INITIATE ART

UGANDA

SOUTH AFRICA
http://f/KOINFEKSI%20TB-HIV.pdfhttp://f/KOINFEKSI%20TB-HIV.pdf


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Infectious or Inflammatory Clinical Criteria for Paradoxical TB-IRIS

Clinical Criteria:At least 1 major clinical criterion or 2 minor clinical criteria are required:

Major criteria1. New or enlarging lymph nodes, fistulas, cold abscesses, or other focal

tissue involvement.2. New or worsening radiological features of TB3. New or worsening central nervous system TB (meningitis or focal

neurological deficit).4. New or worsening TB serositis (pleural effusion, ascites, or pericardial

effusion) or arthritis.5. Signs of tuberculin hypersensitivity (e.g. phlyctenular conjunctivitis,

erythema nodosum).Minor criteria1. New or worsening constitutional symptoms such as fever, night sweats

or weight loss.2. New or worsening respiratory symptoms such as cough, dyspnea, or

stridor.3. New or worsening abdominal pain, discomfort, and/or distension with or

without palpable mass including hepatosplenomegaly4. Resolution of clinical or radiological findings of the suspected IRIS

episode without change in ART, TB treatment, or additional antimicrobialtherapy

Supportive observations1. Conversion of TST negative to positive in patients receiving TB

treatment and ART at time of an IRIS event, or >5x increase frombaseline in interferon release assay (e.g. QuantiFERON, ELISPOT).

t


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s actor or nchildren

Malnourished

Severe CD4 depletion Clinically WHO std III & IV

History of TB


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Guidelines for ART Start in TB/HIVpatients

Guideline/Recommenda

tionCD4 count

strataInterval

SA national ART

programme

2004

CD4 35

2 wks 8 wks8 wks6 mo

DHHS (USA)

2008

CD4 350

2 wks

8 wks8 wks8 24 wks ordefer

British 2010 CD4


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BCG-IRISWHO currently recommends administering

a single dose of BCG vaccine to all infantsliving in areas where tuberculosis is highlyendemic as well as to infants and childrenat particular risk of exposure to

tuberculosis in countries with lowendemicity.

BCG vaccine is contraindicated in people

with impaired immunity, and WHO does notrecommend BCG vaccination for childrenwith symptomatic HIV infection.


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N l t ft BCG


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Normal events after BCG G. HusseySATVI,UCT

BCG IRIS


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BCG IRIS

Courtesy: MarkCotton


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THANKYOU

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